2060-LB: Erythropoietin Regulation of Fat Mass and Glucose Tolerance Mediated by Receptor Expression in Adipose Tissue

The cytokine erythropoietin (EPO) is known for the regulation of red blood production, but its receptor (EpoR) is expressed beyond hematopoietic tissues. Studies in animal models have suggested that EPO regulates glucose homeostasis and fat mass accumulation. To assess EPO metabolic activity, wild-type mice (WT, C57BL/6) and mice lacking EPOR in adipose tissue, ΔEpoR_Adipo (using Adipo-Cre) and ΔEpoR_aP2 (using aP2-Cre), were fed a high-fat diet (HFD, 60% kCal fat) and treated with EPO (3000U/kg 3X per week) or saline for 3 weeks at ages 3, 4, and 6 months. Endogenous EPO regulated fat mass in WT mice, and ΔEpoR_Adipo and ΔEpoR_aP2 mice had increasing trends in fat mass accumulation, becoming significant in older mice. EPO treatment increased hematocrit and decreased fat mass accumulation and body weight in WT male mice at 6 months, showing EPO protection against diet induced obesity (DIO) in male mice while estrogen in female mice protects against DIO. ΔEpoR_Adipo and ΔEpoR_aP2 mice had increased GTT indicating that endogenous EPO activity in adipose tissue improves glucose tolerance. EPO treatment decreased GTT in WT mice. EPO treatment in ΔEpoR_Adipo and ΔEpoR_aP2 mice decreased GTT at 3 months and only in female mice at 4 months that was diminished at 6 months. This demonstrates that with age, adipose tissue response to EPO treatment improves glucose tolerance in a sex dimorphic manner, beginning in male mice at 4 months of age and then in female mice to a lesser extent by 6 months of age. Overall, these findings highlight the potential role of EPO in metabolic regulation beyond erythropoiesis and the contribution of sex and EpoR in adipose tissue in mice to regulate fat mass accumulation and glucose tolerance. Further research into the molecular mechanisms by which EPO signaling influences glucose and lipid metabolism may lead to new therapeutic strategies for the treatment of metabolic disorders such as obesity and type 2 diabetes.